Prolongation of the electrocardiogram QT interval by drugs has been currently concerned, and it is desired to evaluate whether a drug has or has not the action at an early stage of development of the drug, as it is also mentioned in the guideline of ICH. The electrocardiogram QT interval is the time from the start of the depolarization of the ventricle to the end of the repolarization thereof, and when the QT interval is prolonged by a drug or the like, polymorphic ventricular tachycardia of the type called torsades de pointes (TdP) may be induced. When this arrhythmia is induced, a fainting attack may be caused, and it may shift to ventricular fibrillation, which may be fatal one. As for the prolongation of the QT interval and the induction of TdP by drug administration, many reports have been made on antiarrhythmic drugs belonging to the class Ia according to the Vaugham Williams classification. However, in recent years, the prolongation of QT interval and induction of TdP are becoming to be reported for non-circulatory drugs including antibiotics such as erythromycin, antihistamines such as terfenadine and astemizole, and so forth. Furthermore, TdP may be induced by an interaction between drugs. Therefore, for all the compounds being developed as drugs for humans, it is necessary to examine the influence on the electrocardiogram QT interval as one of pharmacological safety tests.
Prolongation of the electrocardiogram QT interval means prolongation of the action potential duration of ventricular muscles. The ionic current participating in the repolarization of ventricular muscle action potential is a delayed rectifier potassium current (IK), and if IK is suppressed, the action potential duration is prolonged. Most of the drugs which prolong the electrocardiogram QT interval are considered to suppress the HERG channel, which passes the rapid component of IK (IKr).
As for in vivo evaluation system for the prolongation of electrocardiogram QT interval, the evaluation is performed in anesthetized dogs and awaken dogs as a pharmacological safety test. However, use of dogs for in vivo evaluation of compounds under searching is difficult, in view of experimental technique and required amounts of compounds. Therefore, evaluation of electrocardiogram was investigated in smaller animals (Non-patent document 1). When E4031, which is considered to selectively suppress IKr, was examined by using anesthetized rabbits, guinea pigs, rats and mice, prolongation of the QT interval by E4031 was observed in rabbits and guinea pigs, whereas it was not observed in rats and mice.
It is considered that the reason why rats and mice cannot be used for evaluation of the QT interval is that the ion channel of them relating to the QT interval is different from that of humans, and it has also been considered that hamsters, which are also rodents, could not also be used for the evaluation.
Further, guinea pigs showed prolongation of the QT interval only in a small degree, and they were considered less sensitive. Rabbits showed high sensitivity and TdP-like ventricular tachycardia, and thus were considered favorably sensitive animals for the evaluation. However, they had a large body weight (about 2 kg), and therefore they were considered to be unsuitable for multi-specimen evaluation.
Non-patent document 1: J. Toxicol. Sci., 23, 344, 1998